Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice
Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice
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DOI：
10.1073/pnas.0506982103
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发表时间：
2006-01-24
影响因子：
11.1
通讯作者：
Edwards, PA
中科院分区：
文献类型：
--
作者：
Zhang, YQ;Lee, FY;Edwards, PA
法尼醇X受体（FXR）在维持胆汁酸和胆固醇稳态中起重要作用。在这里，我们证明了FXR也调节葡萄糖代谢。通过合成激动剂GW 4064激活FXR或通过腺病毒介导的基因转移在肝脏过度表达组成型活性FXR显著降低糖尿病db/db和野生型小鼠的血糖水平。与这些数据一致，FXR敲除小鼠表现出葡萄糖耐受不良和胰岛素不敏感。我们进一步证明了db/db小鼠中FXR的激活通过一种涉及增强胰岛素敏感性的机制抑制了肝致凋亡基因并增加了肝糖原合成和糖原含量。鉴于其在协调调节葡萄糖和脂质代谢中的核心作用，我们认为FXR激动剂是治疗糖尿病的有前途的治疗剂。
Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.